Visceral leishmaniasis (VL) remains a major health problem in India. To understand the complex pathogenesis of VL, TMRC examined key questions in epidemiology, immunology and genetics of disease. We developed the resources, infrastructure and manpower necessary for long term research activities. We achieved the major objectives of all 3 projects, obtaining interesting results that have mostly been brought to the scientific community working in related fields. In TRMC II we want to build on the results of TMRC I, to gain greater understanding of the evolution of the human host/pathogen relationship. TMRC II has therefore been divided into 4 major projects with 4 core facilities. Project 1 will be on the determinants of disease progression and role of latent infection in transmission and will study the role of asymptomatic infection in VL at clinical and public health levels. By generating this evidence we expect to be able to inform control programs, as well as clinical decision-making, to decrease spread of disease in the endemic region. We will also be investigating the role of other NTDs in coinfection with VL. Project 2 constitutes studies of the sand fly vector to improve currently inadequate vector control efforts. This project will test a number of hypotheses, challenging current conventions related to the sand fly vector of VL in Bihar, P. argentipes. Project 3 on immune regulation in VL will continue work aimed at understanding the ever evading immunosuppressive pathways that account for severe progression and fatal outcome of untreated VL. In TMRC I, we demonstrated that whole blood of active VL has the capacity to produce antigen specific IFNg and IL-10, which is biologically active in preventing parasite killing. We want to learn how to subvert the activity of IL-10. Project 4 will carry forwad major findings from a GWAS undertaken in TMRC I to determine the molecular and cellular action of HLA class II molecules, which will have major implications for therapeutic intervention and vaccine design. In addition to these projects, there will be a Scientific and Administrative Core A; a Data Management and Biostatistics Core B; a Demographic Surveillance System (DSS) Core C covering over 125,000 people in Muzaffarpur in 2 phases; and a Molecular Typing and Diagnostics Core D.